PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3
The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP‐I), a biomarker supporting the prediction of drug‐drug interactions ( DDI s) involving hepatic organic anion transporting polypeptide 1 B ( OATP 1 B ), using clinical DDI data with an OATP 1 B inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP 1 B s ( K i,u,OATP1Bs ) and multidrug resistance‐associated protein two‐mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively, from previous reports. Sensitivity analysis demonstrated that the K i,u,OATP1Bs and biosynthesis rate of CP‐I affected the magnitude of the interaction. K i,u,OATP1Bs values optimized by nonlinear least‐squares fitting were ~0.5‐fold of the initial value. It was determined that the blood concentration‐time profiles of four statins were well‐predicted using corrected individual K i,u,OATP1B values (ratio of in vitro K i,u(statin) / in vitro K i,u(CP‐I) ). In conclusion, PBPK modeling of CP‐I supports dynamic prediction of OATP1B‐mediated DDIs.